Dupuytren’s disease, a fibroproliferative disease, affects the palmar fascia of the hand. It is thought to be of autosomal dominant genetic origin with variable penetrance (the frequency with which a heritable trait is manifested by individuals carrying the principal gene or genes conditioning it).
Dupuytren’s disease starts with the development of well defined localized nodules and skin pits on the palm. The nodules have an abundance of myofibroblasts and limited collagen content, and have a rich blood supply. They tend to regress spontaneously, to be replaced by a fibrotic cord that contains a significant amount of type I and III collagen and only sparse myofibroblasts. As the cord ages, it tends to contract in length, producing the characteristic fixed-flexion contracture that can develop in a single joint or in multiple joints, and affects the fingers of both hands. Over a period of years, there is a loss of hand function.
There are no biomarkers for this disease. As it progresses, activities of daily living are seriously affected.
There is no cure. Primary treatment is surgery. There are no approved nonsurgical options. Attempts to use physiotherapy, radiation, vitamin E, steroid injections, and enzymes such as pepsin, trypsin, and hyaluronidase have all failed to produce effective outcomes.
Results of surgery mirror the severity of the presurgical functional limits, i.e., the worse the disease before surgery, the less satisfactory the final results. Also, surgery does not provide a cure. Dupuytren’s contractures commonly recur after surgery. Typically, surgery is performed late in the disease process, as the side effects and post surgical healing times are considerable.
The typical patient presenting for surgery is a white man in his late 50s who has had Dupuytren’s disease for about a decade. The disease is typically bilateral, with one hand more severely affected than the other.
Results of surgery were reported in a 1990 article. The study involved 1,150 patients. The best results were seen in the MP (metacarpophalangeal) joint, with 70 percent to 89 percent satisfactory outcome. The PIP (proximal interphalangeal) joint had less satisfactory results, with full correction of contractures achieved in 13 percent to 29 percent of cases. Residual contractures of 22 degrees to 35 degrees were common. Complications occurred in 17 percent to 30 percent of patients and included inflammation, hematoma, ischemic skin necrosis, wound infections, granuloma formation, neuropraxia, flexor tendon and ligament injury, joint stiffness, and poor strength.
Unmet need drove researchers to search for another option.
This research has now apparently been fruitful. On Sept. 16, 2009, the Arthritis Advisory Committee of the FDA recommended by unanimous vote that the FDA grant full approval to a novel, first-in-class biologic that will be sold under the brand name Xiaflex. Designated an orphan drug, Xiaflex is a mixture of two separate collagenase molecules that are isolated from the bacterium Clostridium histolyticum. Collagenase activity was first discovered over 50 years ago in the medium of cultures of these bacteria.
Xiaflex consists of type I and type II collagenases. Both enzymes are isolated and purified from the bacteria’s culture medium. These two different molecules are immunologically cross-reactive but differ in their preferred cleavage site on the collagen molecule. They work better together than alone on the interstitial collagen which constitute the bands of the Dupuytren’s contracture.
Treatment consists of an injection of 0.58 mg of the mixture into the contracted cord, followed by a finger extension procedure to facilitate cord disruption for patients whose cords do not separate spontaneously. If, after four weeks, the contracture has not responded adequately, a second injection and extension procedure may be attempted. Almost 1,100 subjects have received at least one injection of Xiaflex in 13 separate trials, including one phase 1, three phase 2, and nine phase 3 trials. Some were open-label extension trials.
The recommendation of the advisory committee was based on three controlled, randomized, double-blinded trials involving 400 patients. The primary endpoint was a reduction of contracture to 5 degrees or less in the primary joint treated. Subjects treated with Xiaflex had a greater reduction in baseline contracture, a greater increase in range of motion, and a more rapid time to achieve this reduction when compared to placebo injections.
In fact, in those actively treated, mean range-of-motion (ROM) improvements in MP joints in the three pivotal trials were 83.7 degrees, 79.5 degrees, and 87.9 degrees. The PIP joints improved 74.9 degrees, 72.8 degrees, and 101 degrees. To look at the results another way, the mean improvement in ROM was 40.6 degrees in the active arm versus 3.7 degrees in the placebo in study 1 (the largest trial, which included three quarters of the subjects). This results were similar in the other, much smaller, trials.
Overall, 87 percent of subjects were either “very satisfied” or “quite satisfied” with the results in the active trial versus 31.7 in the placebo group. Annual estimated rate of recurrence of contracture, evaluated in all patients who achieved a reduction of contracture to less than 5 degrees, is 6.7 percent. This compares with a postsurgical recurrence rate of an average of 33 percent (from historical studies).
Xiaflex was well tolerated in clinical trials, with the most common adverse events occurring locally and of mild-to-moderate severity. As a foreign protein, Xiaflex was expected to cause an antibody response. These expectations were fulfilled, but the antibodies were of little consequence because of the limited nature and infrequency of this injection. Adverse events such as vascular leakage and neutrophil chemotaxis are also expected because of the mechanism of action of Xiaflex.
If final FDA approval is granted, Xiaflex will offer a repeatable, much-less-invasive option that results in a better overall outcome in a shorter amount of time for patients suffering from Dupuytren’s disease. Although the procedure is relatively simple, health plans may wish to look at who should be approved to perform it, as most physicians in the clinical trials were hand surgeons (81 percent).
Because it is less invasive than surgery, it is likely that patients will seek therapy at an earlier stage of the disease. Although the price has not been announced, it is likely to be significantly less expensive than the surgical options, as it avoids operating room and surgeon’s charge and is replaced with a much lower procedural code.
The development of Xiaflex marks an answer to a huge unmet need for people suffering from Dupuytren’s disease. It demonstrates how long (in this case 50 years) basic scientific observations may take to become part of Tomorrow’s Medicine.